Osteoporosis primarily affects postmenopausal women. However, young women with estrogen deficiency also are at increased risk for low bone density. We assessed bone density and associated risk factors for reduced bone density in young, estrogen-deficient women using primary ovarian insufficiency (POI) as the disease model. We conducted a cross-sectional study at a tertiary care research center. We studied 442 women with POI, 70 concurrent control women, and 353 matched controls from the NHANES III study. We measured bone mineral density (BMD) using dual-energy x-ray absorptiometry. Patients on average had 2-3% lower BMD at L1-L4, femoral neck, and total hip. The statistically significant modifiable risk factors for BMD below the expected range for age (Z-score <-2) were: more than 1-yr delay in diagnosis of the associated estrogen deficiency, low (<32 ng/ml) vitamin D levels, estrogen replacement nonadherence, low calcium intake, and lack of exercise. As compared to Caucasians, African-American and Asian women with POI were 3.18 and 4.34 times more likely, respectively, to have Z-scores below -2. Race was an overall risk factor, but on regression modeling, not an independent predictor of low bone density. From this work we conclude that women with POI have lower bone density compared to regularly menstruating control women. Compared to Caucasians, minority women with estrogen deficiency are more likely to have BMD below the expected range for age. This racial disparity appears to be related to a combined effect of several modifiable risk factors. Delay in diagnosis of POI also contributes to reduced bone density by delaying proper therapy. We also examined factors associated with emotional well-being in women with spontaneous primary ovarian insufficiency (POI) using a cross-sectional and case-control study. We studied 100 women diagnosed with spontaneous 46,XX POI at a mean age of 32.4 years and 60 healthy control women of similar age by administering validated self-reporting psychosocial instruments. The main outcome measures of our study were illness uncertainty, stigma, goal disengagement/re-engagement, purpose in life, positive and negative affect, depression, and anxiety. Compared with controls, women with spontaneous POI scored adversely on all measures of affect. Illness uncertainty and purpose in life were significant independent factors associated with anxiety;stigma and purpose in life were the significant independent factors associated with depression;and goal re-engagement and purpose in life were significantly and independently associated with positive affect. This evidence supports the need for prospective studies. Our findings are consistent with the hypothesis that clinicians could improve the emotional well-being of their patients with POI by 1 informing them better about their condition, 2 helping them to feel less stigmatized by the disorder, and 3 assisting them in developing alternative goals with regard to family planning as well as other goals. We also tested the hypothesis that women with spontaneous POI differ from control women with regard to perceived social support and investigated the relationship between perceived social support and self-esteem. We studied 154 women diagnosed with spontaneous POI at a mean age of 27 years and 63 healthy control women. We found that women with POI had significantly lower scores than controls on both the perceived social support scale and the self-esteem scale. The findings remained significant after modeling with multivariate regression for differences in age, marital status, and having children. There was a significant positive correlation between self-esteem scores and perceived social support in patients. We found no significant differences in perceived social support or self-esteem related to marital status, whether or not the women had children, or time since diagnosis. This evidence supports the need for prospective controlled studies. Strategies to improve social support and self-esteem might provide a therapeutic approach to reduce the emotional suffering that accompanies the life-altering diagnosis of spontaneous POI. We studied the psychosocial implications for teens that develop POI and their parents. The normal developmental tasks and roles of adolescence are altered by a diagnosis of a reproductive disorder. The crisis of impaired fertility affects both parent and child, stressing the family system. For the adolescent girl, a reproductive disorder has an impact on her developing sense of self, body-image, and sexuality, which, in turn, can affect her self-esteem and relationships with others. Because of the sexual nature of a reproductive disorder, feelings of embarrassment or protectiveness are often engendered that can make it difficult for families to discuss. Nonetheless, families do best with openness and honesty regarding the condition and should be discouraged from keeping the diagnosis a secret. Adolescence encompasses a broad spectrum of emotional maturity, which needs to be considered by parents and clinicians when communicating information. Understanding that the family is an emotional unit, a family systems approach to deal with health issues is most appropriate. In this context, parents need to first deal with their own feelings about the diagnosis, before they can help their child. Secondly, parents must be provided with tools to build an ongoing conversation with their child that will avoid stigmatizing her condition and handicapping her growth into healthy adulthood. The goal for parent and clinician is to help the adolescent girl formulate positive self-esteem and body image, despite impaired fertility. As part of an international collaboration we investigated the genetic mechanisms of POI. Bone morphogenetic protein-15 (BMP15) is selectively synthesized by oocytes as a pre-proprotein and is considered an ovarian follicle organizer whose adequate function is critical for female fertility. Missense mutations were reported in POI but their biological impact remained unexplored. Here, screening of 300 unrelated women with idiopathic overt POI. This led to the identification of six heterozygous BMP15 variations in 29 of them. All alterations were nonconservative and included one insertion of three nucleotides (p.L262_L263insL) and five missense substitutions. Except for the p.S5R located in the signal sequence, the other variants (p.R68W, p.R138H, p.L148P, and p.A180T) localized in the proregion, which is essential for the processing and secretion of bioactive dimers. The mutations p.R68W, p.L148P, and the novel p.R138H led to marked reductions of mature protein production. Their biological effects, evaluated by a novel luciferase-reporter assay in a human granulosa cell (GC) line, were significantly reduced. Cotransfection experiments of defective mutants with equal amounts of wild-type BMP15 cDNA, thus reproducing the heterozygous state seen in patients, did not generate a complete recovery of wild-type activity. We conclude that heterozygous BMP15 mutations associated with the early onset of overt POI lead to defective secretion of bioactive dimers. These findings support the concept that an adequate amount of BMP15 secreted in the follicular fluid is critical for female fertility. We propose to consider the screening of BMP15 mutations among the analyses for the prediction of POI risk. We are also investigating methods that might improve fertility in women with POI. We found that a regimen of 100 microgram per day of transdermal estradiol replacement achieves normal serum LH levels in approximately one-half of women with spontaneous POI. Theoretically, physiologic estradiol replacement therapy might improve follicle function in these women. We are planning controlled studies.